Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]>CN(C=O)C>[CH:38]([O:37][C:35]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1)=[O:36])([CH3:40])[CH3:39]
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
500 mg (1.30 mmol) of 1-(4′-aminobiphenyl-4-sulfonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid were dissolved in 3 ml of DMF, after which the solution was cooled down to 0° C. in an ice bath and 2.6 mmol of pyridine were added. After the mixture had been stirred at 0° C. for 15 min, 2 mmol of isopropyl chloroformate in 3 ml of DMF were added. The reaction solution was then stirred at RT for a further 2 h. The crude product was purified using chromatographic methods.
Reaction SMILES: [CH:1]([O:4][CH2:5][C:6]([OH:8])=O)([CH3:3])[CH3:2].CC(C)(C)C(Cl)=O.[Cl-].[Li+].[CH2:18]([C@H:25]1[CH2:29][O:28][C:27](=[O:30])[NH:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1.C(N(CC)CC)C>[CH2:18]([C@H:25]1[CH2:29][O:28][C:27](=[O:30])[N:26]1[C:6](=[O:8])[CH2:5][O:4][CH:1]([CH3:2])[CH3:3])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CC(C)OCC(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)OCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -25 °C
Reaction time: 5 h
Yield: 56.8 %

Procedure:
A solution containing 98 g of 2-isopropoxyacetic acid and 360 ml of triethylamine in tetrahydrofuran (4L) was cooled to −25° C. After 92 ml of 2,2-dimethylpropanoyl chloride was dropwise added, the reaction solution was stirred at −20° C. for 5 hours. Then, 50 g of anhydrous lithium chloride and 120 g of (4S)-4-benzyl-1,3-oxazolidin-2-one were successively added, and stirring was continued at room temperature overnight. Then, the reaction solution was filtered and evaporated. The residue was dissolved in 2 L of ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate), to give 106.6 g of (4S)-4-benzyl-3-(2-isopropoxyacetyl)-1,3-oxazolidin-2-one as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[CH:15]=[C:14]([CH2:25][CH3:26])[N:13]=[C:12]1[O:27][CH3:28])=[O:10])C1C=CC=CC=1.Cl[C:30]([O:32][CH3:33])=[O:31]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:33]([O:32][C:30]([C:15]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[N:11]([C:9]([O:8][CH3:1])=[O:10])[C:12]([O:27][CH3:28])=[N:13][C:14]=1[CH2:25][CH3:26])=[O:31])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)Cl
Reactant: CCC1=CC(c2ccc(F)c(F)c2)N(C(=O)OCc2ccccc2)C(OC)=N1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)N(C(=O)OC)C(OC)=N1
Yield: 135 %

Procedure:
To a well stirred solution of (benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(3,4-diflurophenyl)pyrimidine (0.6 g, 1.5 mmol) and 4-(N,N-dimethylamino)pyridine (0.32 g, 2.66 mmol) in CH2Cl2 (6 mL) was added methyl chloroformate (0.2 mL, 2.66 mmol) at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel with 3:1 Petroleum ether/EtOAC as the eluting system to obtain 0.45 g (78% yield) of (−)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[methoxy-carbonyl]pyrimidine as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH2:10][C:11]([OH:13])=O.Cl.[CH3:15][NH:16][O:17][CH3:18]>C(Cl)Cl>[CH3:18][O:17][N:16]([CH3:15])[C:11](=[O:13])[CH2:10][O:9][CH3:8]
Reactant: COCC(=O)O
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)N(C)OC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 64.1 %

Procedure:
Triethylamine (115 mL) was added to a solution of methoxyacetic acid (35.0 g, 389 mmol) in CH2Cl2 (1200 mL) at room temperature. N,O-dimethylhydroxylamine hydrochloride (45.5 g, 467 mmol) was added, and after stirring for 5 min, the suspension was cooled to 0° C. Ethyl diazocarboxylate (EDC) (81.7 g, 428 mmol) was then added and the reaction mixture was stirred overnight while allowing it to warm to room temperature. The mixture was poured into a separatory funnel and diluted with CH2Cl2 (500 mL). The organic layer was washed with 1 N HCl (2×300 mL), saturated aqueous NaHCO3 solution (2×300 mL), and brine (300 mL). The resulting solution was dried over MgSO4, filtered and concentrated in vacuo. The product was purified by column chromatography on a short column of silica gel (5% methanol in CH2Cl2) to afford N,2-dimethoxy-N-methylacetamide (33.2 g, 64% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 4.20 (s, 2H), 3.67 (s, 3H), 3.45 (s, 3H), 3.17 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 173.0, 69.7, 69.4, 61.4, 59.4; LRMS (ESI) m/e 134.1 [(M+H)+, calcd for C5H12NO3 134.1].
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:13][C:14]1[CH:18]=[CH:17][NH:16][N:15]=1.O=[C:20]([CH2:27][CH2:28][CH3:29])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH2:27]([C:20]1[NH:13][C:14]2=[N:15][NH:16][CH:17]=[C:18]2[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[C:2]([F:12])([F:11])[F:1])[C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:28][CH3:29]
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: CCCC(=O)CC(=O)OCC
Product: CCCC1=C(C(=O)OCC)C(c2ccccc2C(F)(F)F)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2-trifluoromethylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4][CH2:3]1.[F:19][C:20]([F:36])([F:35])[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:32][C:31]([CH:33]=O)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.NCCC(O)=O.CO.C(Cl)Cl>C(O)(=O)C>[F:36][C:20]([F:19])([F:35])[O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[S:32][C:31]([CH:33]=[C:3]3[C:2](=[O:1])[N:6]([CH:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4]3)=[CH:30][CH:29]=2)=[CH:26][CH:27]=1
Reactant: O=Cc1ccc(-c2ccc(OC(F)(F)F)cc2)s1
Reactant: O=C(O)C(Cc1ccccc1)N1C(=O)CNC1=S
Agent: NCCC(=O)O
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(O)C(Cc1ccccc1)N1C(=O)C(=Cc2ccc(-c3ccc(OC(F)(F)F)cc3)s2)NC1=S
Temperature: 170 °C

Procedure:
To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.031 g, 0.117 mmol) and 5-(4-trifluoromethoxy-phenyl)thiophene-2-carbaldehyde (0.030 g, 0.117 mmol) in acetic acid 5 mL is added β-alanine (1.042 mg, 0.012 mmol) and heat to 170° C. for 30 min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.035 g, 0.069 mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. 1H-NMR (CD3OD/300 MHz): 7.91 (m, 2H), 7.32 (d, J=9.0 Hz, 2H), 7.14 (m, 5H), 7.02 (m, 2H), 6.47 (s, 1H), 5.64 (dd, J=11.1, 5.4 Hz, 11H), 3.70 (dd, J=14.1, 12.6 Hz, 1H), 3.53 (dd, J=14.1, 5.1 Hz, 1H). MS (ES−, m/z): 501.4 (M−, 100.0).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:21])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:39][C:40]([O:42][CH3:43])=[O:41]>CC(C)=O>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][CH2:39][C:40]([O:42][CH3:43])=[O:41])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)=[O:13]
Reactant: COc1c(C)c(Cc2ccc(O)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1C(=O)N1CCOCC1
Yield: 85.6 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzoyl]morpholine (0.200 g, 0.465 mmol) was dissolved in acetone (30 ml) and after adding thereto anhydrous sodium carbonate (0.077 g, 0.558 mmol) and methyl bromoacetate (0.078 g, 0.512 mmol), the solution was refluxed under heating for 3 hours. The reaction solution was filtered, the filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=1:1) to obtain the titled compound (0.230 g, 0.398 mmol, 86%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[CH2:7][C@@H:6]1[C:8]([O:10]C(C)(C)C)=[O:9]>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[CH2:7][C@@H:6]1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)C[C@H]1C[C@@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C[C@H]1C[C@@H]1C(=O)O

Procedure:
Tert-butyl (1S,2R)-2-(2-methoxy-2-oxoethyl)cyclopropanecarboxylate was dissolved in a mixture of trifluoroacetic acid:methylene chloride (7:3) and stirred at room temperature until the t-butyl ester was removed. The solvent was removed under reduced pressure to give product. 1H NMR (CDCL3) δ 3.70 (s, 3H), 2.35 (d, J=7.5 Hz, 2H) 1.85–1.70 (m, 1H), 1.52–1.49 (m, 1H), 1.39–1.30 (m, 1H), 0.93–0.87 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.[C:7](OC(=O)C)(=[O:9])[CH3:8]>>[C:7]([NH:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nnn[nH]1
Product: CC(=O)Nc1nnn[nH]1
Reaction time: 8 h
Yield: 45.8 %

Procedure:
A mixture of 6.18 g (60 mmoles) of 5-aminotetrazole with 56.3 ml of acetic anhydride was stirred at 20°-25° C. overnight. The so separated white precipitate was recovered by filtration, washed with a small volume of ethyl acetate and dried to give 3.5 g of 5-acetylaminotetrazole (Yield 45.8%). Thereafter, 10 ml of N,N-dimethylformamide and 120 mg of powdery sodium hydroxide were added to 571 mg (4.5 mmoles) of 5-acetylaminotetrazole and the resulting mixture was stirred at 20°-25° C. for one hour. Then, 1.77 g (3 mmoles) of 2,3,3-triiodoallyl-p-toluenesulfonic acid ester were added thereto and stirring was continued for 5 hours. To the reaction mixture was added water, the so separated white crystal was recovered by filtration, washed with a small volume of water and dried to give 578 mg of 5-acetylamino-1-(2',3',3'-triiodoallyl)tetrazole.
Reaction SMILES: [CH2:1]1[CH2:11]CN2C(=NCCC2)C[CH2:2]1.[Cl:12][C:13]1[CH:14]=[C:15]([CH2:19][CH:20]([OH:39])/[CH:21]=[CH:22]/[C@H:23]2[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[N:24]2[CH2:30][C:31]#[C:32][CH2:33][O:34][CH2:35][C:36]([OH:38])=[O:37])[CH:16]=[CH:17][CH:18]=1.IC(C)C>CC(C)=O>[CH:1]([O:37][C:36](=[O:38])[CH2:35][O:34][CH2:33][C:32]#[C:31][CH2:30][N:24]1[C:25](=[O:29])[CH2:26][CH2:27][CH2:28][C@@H:23]1/[CH:22]=[CH:21]/[CH:20]([OH:39])[CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[CH:14]=1)([CH3:11])[CH3:2]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)COCC#CCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1cccc(Cl)c1
Solvent: CC(C)I
Solvent: CC(C)=O
Product: CC(C)OC(=O)COCC#CCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1cccc(Cl)c1
Reaction time: 0.08 h
Yield: 58.8 %

Procedure:
DBU (6.6 μL, 0.044 mmol) was added to a solution of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-hydroxy-but-1-enyl]-6-oxo-piperidin-1-yl}-but-2-ynyloxy)-acetic acid (12 mg, 0.030 mmol) in acetone (0.3 mL). After 5 min, 2-iodopropane (15 μL, 0.15 mmol) was added. After 19 h, the reaction mixture was concentrated in vacuo, 0.5 M aqueous HCl (5 mL) was added and the mixture was extracted with EtOAc (3×5 mL). The combine organic phase was washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL) then dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→3% MeOH/CH2Cl2, gradient) afforded 7.9 mg (60%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:8]=1[Cl:34])[CH3:6])=[O:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:59][NH:60][C:61]([C@H:63]1[CH2:68][CH2:67][CH2:66][N:65]([CH2:69][C:70](O)=[O:71])[CH2:64]1)=[O:62].C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1.C(OCC)(=O)C>[Cl:34][C:8]1[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:70](=[O:71])[CH2:69][N:65]1[CH2:66][CH2:67][CH2:68][C@H:63]([C:61]([NH:60][CH3:59])=[O:62])[CH2:64]1
Reactant: CNC(=O)[C@H]1CCCN(CC(=O)O)C1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CNC(=O)[C@H]1CCCN(CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide (0.45 g, 0.9 mmol) in anhydrous NMP (10 ml) was treated with HBTU (0.48 g, 1.2 mmol), (S)-2-(3-(methylcarbamoyl)piperidin-1-yl)acetic acid (0.21 g, 1.08 mmol) and diisopropylethyl amine (0.47 mL, 2.7 mmol) with stirring at room temperature overnight. To the reaction was added ethyl acetate (100 mL) and the mixture was washed with aqueous saturated sodium bicarbonate (100 mL×3). The organic layer was dried over magnesium sulfate, filtered and evaporated to an off white solid, 0.34 g that was purified by chromatography (silica gel, ethyl acetate and methanol gradient) to afford (S)-1-(2-(2-((2,4-dichloro-3-((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yloxy)methyl)phenyl)(methyl)amino)-2-oxoethylamino)-2-oxoethyl)-N-methylpiperidine-3-carboxamide (36) as a white solid, 0.12 g (20%), that was about 90 pure by LC/MS (+APCI) m/z 682 (M+), 1HNMR (400 MHz, CDCl3) δ 8.60 (m, 1H), 7.60 (m, 2H), 7.50 (m, 1H), 7.30 (m, 1H), 7.35 (m, 1H), 7.19 (m, 1H), 7.04 (m, 1H), 6.92 (m, 1H), 6.81 (m, 2H), 6.70 (broad m, 1H), 5.67 (s, 2H), 5.29 (s, 2H), 4.21 (s, 3H), 4.1 to 1.4 (many multiplets, 19H). 13CNMR (100 MHz, CDCl3) δ 174.4, 170.5, 168.8, 156.8, 156.1, 149.6, 149.0, 138.4, 138.2, 137.0, 136.5, 135.8, 135.3, 130.3, 122.6, 121.7, 120.8, 107.3, 103.1, 67.0, 61.6, 57.5, 56.5, 56.2, 54.3, 53.4, 47.7, 45.4, 41.3, 36.0, 30.9, 26.3, 26.1, 24.5.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH2:17][CH2:18][C:19](O)=[O:20])[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH2:17][CH2:18][C:19]([N:32]([CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[C:29]2[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=2)=[O:20])[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCNc1ccc(OC)cc1
Reactant: COc1ccc(N(CCC(=O)O)C(=O)c2ccc(Cl)cc2)cc1
Product: COC(=O)CCCN(C(=O)CCN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-3-(p-anisidino)propionic acid and methyl 4-(p-anisidino)butyrate and suitable processing produces methyl N-[N-(p-chlorobenzoyl)-3-(p-anisidino)propionyl]-4-(p-anisidino)butyrate (oil), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-3-(p-anisidino)propionyl]-4-(p-anisidino)butyric acid (M.P. 91° to 93°).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[C:9]([N:13]1[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]([CH3:24])[N:15]([CH3:25])[C:14]1=[O:26])(=[O:12])[CH:10]=[CH2:11].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(C(C)C)C(C)C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:25][N:15]1[CH:16]([CH3:24])[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:13]([C:9](=[O:12])/[CH:10]=[CH:11]/[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=2)[C:14]1=[O:26]
Reactant: Fc1cccc(Br)c1
Reactant: C=CC(=O)N1C(=O)N(C)C(C)C1c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1C(c2ccccc2)N(C(=O)/C=C/c2cccc(F)c2)C(=O)N1C
Temperature: 110 °C
Yield: 76 %

Procedure:
A solution of 1-bromo-3-fluorobenzene (525 mg, 3 mmole), (4 R, 5 S)-1-acryloyl-3,4-dimethyl-5-phenylimidazolidin-2-one (500 mg, 2 mmole), Pd(OAc)2 (22 mg, 0.10 mmole), P(o-tolyl)3 (61 mg, 0.20 mmole), and (i-Pr)2NEt (0.73 mL, 4.2 mmole) in dry DMF (10 mL) was degassed (3×vacuum/N2 purge) then heated to 110° C. After 2 hr the mixture was cooled and poured into EtOAc. The resulting mixture was washed with H2O (3×), and the combined aqueous layers were back-extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered through a plug of silica gel, and concentrated. The residue was taken up in 1:1 Et2O/hexanes (10 mL) and cooled at −20° C. overnight. The solid was collected and dried in vacuo to afford the title compound (514 mg, 76%): 1H NMR (300 MHz, CDCl3) δ 8.18 (d, J=15.9 Hz, 1 H), 7.64 (d, J=15.9 Hz, 1 H), 7.15-7.45 (m, 8 H), 6.98-7.10 (m, 1 H), 5.42 (d, J=8.5 Hz, 1 H), 3.88-4.03 (m, 1 H), 2.88 (s, 3 H), 0.85 (d, J=6.6 Hz, 3 H); MS (ES) m/e 339 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]1[CH2:29][N:28]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:26](=[O:27])[CH2:25]1.Cl>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3([CH2:22][N:33]4[CH2:34][CH2:35][CH:30]([N:28]5[CH2:29][CH2:24][CH2:25][C:26]5=[O:27])[CH2:31][CH2:32]4)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: O=C1CCCN1C1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCO
Product: O=C1CCCN1C1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)CC1
Yield: 22.5 %

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (400 mg, 1.260 mmol), 4-(N-2-pyrrolidinone)piperidine hydrochloride (493 mg, 4.407 mmol), absolute ethanol (16 ml), activated 3 Å molecular sieves (400 mg), titanium (IV) isopropoxide (1.86 ml, 6.30 mmol) and STAB (2.27 g, 10.71 mmol) were reacted in accordance with the general procedure D. The isolated waxy solid was purified by column chromatography on silica eluting with DCM(95):MeOH(4):NH3(1) to give the title compound as a pale yellow oil (133 mg, 22%). 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.86 (d, 2H), 4.02 (t, 2H), 3.83-3.71 (m, 3H), 3.52 (dt, 2H), 3.32 (t, 2H), 2.63 (t, 2H), 2.53 (br s, 4H), 2.41-2.30 (m, 6H), 2.18 (dt, 2H), 2.12-1.36 (m, 16H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.I[CH:10]1[CH2:13][O:12][CH2:11]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH:10]2[CH2:13][O:12][CH2:11]2)[CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: IC1COC1
Product: O=c1ccc(Br)cn1C1COC1

Procedure:
The title compound was prepared from 5-bromopyridin-2(1H)-one and 3-iodooxetane following a procedure analogous to that described for Intermediate 22.
Reaction SMILES: [O:1]=[C:2]1[N:9]2[C:5]([CH2:11][CH2:12][CH2:13][C:14]([O:16]CC3C=CC=CC=3)=[O:15])([CH2:6][CH2:7][C:8]2=[O:10])[CH2:4][CH2:3]1.[H][H]>O1CCCC1.[Pd]>[O:10]=[C:8]1[N:9]2[C:5]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])([CH2:4][CH2:3][C:2]2=[O:1])[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: O=C(CCCC12CCC(=O)N1C(=O)CC2)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)CCCC12CCC(=O)N1C(=O)CC2

Procedure:
A solution of 1.0 g (0.0032 mole) tetrahydro-3,5-dioxo-1H-pyrrolizine-7a(5H)-butanoic acid, benzyl ester, prepared in Example I in tetrahydrofuran (30 ml) is treated with hydrogen in the presence of 0.1 g of a 20% Pd/C catalyst. The resulting solution is filtered to remove the catalyst and the product crystallizes upon concentration. Recrystallization from acetonitrile yields tetrahydro-3,5-dioxo-1H-pyrrolizine-7a(5H)-butanoic acid with a melting point of 178°-180° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH3:20].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C(Cl)c1ccccc1
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1ccccc1

Procedure:
Using the general method of Example 1, 1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.8 mmol) was reacted with benzoyl chloride (0.26 g, 1.8 mmol) to provide N1-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzamide as a solid, m.p. 164-170° C. 1H NMR (500 MHz, DMSO-d6) δ 8.47 (t, J=6.0 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.59 (dd, J=8.0, 1.2 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 2H), 7.38 (dt, J=8.0, 1.2 Hz, 1H), 7.17 (dt, J=8.0, 1.2 Hz, 1H), 6.48 (broad s, 2H), 4.53 (t, J=7.0 Hz, 2H), 3.31 (q, J=6.0 Hz, 2H), 2.60 (s, 3H), 1.88 (quintet, J=7.0 Hz, 2H), 1.68 (quintet, J=7.0 Hz, 2H); MS (EI) m/e 373.1903 (373.1903 calcd for C22H23N5O).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:19])([CH:16]([SH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.ClCCl.C(N(CC)CC)C.[CH2:30]([N:32]([CH2:36][CH3:37])[C:33](Cl)=[S:34])[CH3:31]>O>[CH2:30]([N:32]([CH2:36][CH3:37])[C:33](=[S:34])[S:18][CH:16]([C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([OH:19])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[CH3:17])[CH3:31]
Reactant: CC(S)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CCN(CC)C(=S)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCN(CC)C(=S)SC(C)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 30.9 %

Procedure:
(2RS,3RS)-2-(2,4-difluorophenyl)-3-mercapto-1-[1H-1,2,4-triazol-1-yl]-2-butanol (0.3 g) was added to dichloromethane (5 ml), to which triethylamine (0.16 ml) was added under ice-cooling, and then, N,N-diethylthiocarbamoyl chloride (0.18 g) was added. The resultant solution was stirred for 1 hour at room temperature. Thereafter, water (20 ml) was added to the reaction mixture. The resultant mixture was then extracted with dichloromethane (40 ml). The extract was washed with water (20 ml), dried (MgSO4) and distilled off to remove the solvent under reduced pressure. The residue was purified by a silica gel column chromatography (2.9×30cm, eluent: ethyl acetate-dichloromethane=1:3). The objective fractions were concentrated. Hexane was added to the residue to give the compound (1), i.e., [(2RS,3RS)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2butyl] N,N-diethyldithiocarbamate (0.13 g) as colorless needles.